Tau is a microtubule associated protein (MAP) primarily expressed in neurons that has traditionally been thought to promote microtubule assembly and stability in the axon. However, recent in vitro motility experiments have also demonstrated that tau is a potent inhibitor of processive kinesin movement along microtubules. These results present an interesting paradox, namely - how can kinesin processively transport its cargo along microtubules in the presence of tau, which is highly expressed in neurons and localized to the axon? The answer to this question has important implications for axonal transport, a critical process in neurons required for the efficient delivery of organelles, proteins, nucleic acids, and small molecules synthesized in the cell body to their site of function in distal regions of the axon. Defects in any one of the protein components in the axonal transport machinery, which includes microtubules, members of the kinesin superfamily of motor proteins, a variety of adapter molecules that link kinesin to its intracelleualr cargo, and MAPs such as tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and ALS. We propose two interrelated hypotheses regarding the interaction of tau and microtubules in regulating kinesin motility during axonal transport: 1) Tau bound to different sites on microtubules have distinct functions, and only tau bound to the exterior site on polymerized microtubules inhibits kinesin motility. 2) Specific post-translational modifications of tubulin such as acetylation promote the binding and motility of kinesin in neuronal axons even in the presence of tau. PUBLIC HEALTH RELEVANCE: Defects in any one of the protein components in the axonal transport machinery, including MAPs such as tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and ALS. Thus understanding tau's role in modulating kinesin motility in the neuron is imperative to elucidating the molecular mechanisms of axonal transport in both normal and pathological states.